Atezolizumab regimen fails to extend PFS in triple-negative breast cancer subset
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The addition of atezolizumab to paclitaxel failed to significantly prolong PFS for patients with PD-L1-positive metastatic triple-negative breast cancer, according to phase 3 study results presented during ESMO Virtual Congress 2020.
“We have known for some years now that triple-negative breast cancer is a heterogenous disease entity and we are aware that the prognosis has not changed over the years. There remains a high unmet clinical need,” David W. Miles, MD, MB, BS, BSc, FRCP, professor and medical oncologist at Mount Vernon Cancer Centre in Northwood, U.K., said during his presentation.
“Some triple-negative tumors have immune infiltrate and high PD-L1 expression, providing the rationale for immunotherapy in triple-negative breast cancer,” Miles added. “The IMpassion130 trial established atezolizumab [Tecentriq, Genentech/Roche] as a new standard of care for PD-L1-positive metastatic triple-negative breast cancer, and subsequent trials in metastatic triple-negative breast cancer have assessed different immunotherapy agents, alternative chemotherapy backbones and additional patient populations.”
In the current IMpassion131 trial, Miles and colleagues sought to assess atezolizumab in combination with first-line paclitaxel among patients considered for first-line chemotherapy with a treatment-free interval of at least 1 year. Patients previously treated with a taxane-based chemotherapy also were eligible if they had measurable disease and a good performance status.
Investigators randomly assigned 651 patients 2:1 to 90 mg/m² paclitaxel on days 1, 8 and 15 of each 28-day treatment cycle in combination with either 840 mg atezolizumab or placebo on days 1 and 15 until disease progression or unacceptable toxicity. Patient stratification factors included PD-L1 status, prior taxane-based therapy, liver metastases and geographic region.
Nearly half (48%) of the study participants received prior taxane-based therapy, 45% had PD-L1-positive tumors, 31% had de novo disease and 27% had liver metastases.
Investigator-assessed PFS, tested hierarchically in the PD-L1-positive population followed by the intention-to-treat-population, served as the primary endpoint. Secondary endpoints included OS and overall response rate.
Results showed the addition of atezolizumab to paclitaxel did not significantly improve PFS or OS among either study population. Researchers reported median PFS of 6 months with atezolizumab vs. 5.7 months with placebo (stratified HR = 0.82; 95% CI, 0.6-1.12) among the PD-L1-positive group and 5.7 months vs. 5.6 months (stratified HR = 0.86; 95% CI, 0.7-1.05) among the intention-to-treat population.
“Not surprisingly, when we looked at PFS among the subgroups within the PD-L1-positive group, there was not a significant effect. There also were no great clues about adverse events or benefit in any of the subgroups analyzed,” Miles said. “A small improvement was observed in the intention-to-treat-population overall; however, this was not subjective to formal testing and did not approach significance.”
Median OS favored the placebo regimen in both the PD-L1-positive subgroup (28.3 months vs. 22.1 months; HR = 1.12; 95% CI, 0.76-1.65) and the intention-to-treat population (22.8 months vs. 19.2 months; HR = 1.11; 95% CI, 0.87-1.42). The OS analysis only accounted for 47% of deaths in the intention-to-treat-population, Miles said.
“Clearly more follow-up on OS is required,” he said. “Given these findings, we needed to explore whether the delivery of chemotherapy is compromised and whether toxicity is an issue. When we looked at exposure of treatment, what gave us confidence that we were delivering adequate chemotherapy was that the mean and median dose intensities were similar, as was the median total accumulative dose. Overall, the exposure to treatment was similar between the two groups.”
The placebo and atezolizumab groups had similar rates of grade 3/grade 4 adverse events (43% vs. 49%) and grade 5 adverse events (2% for both), with safety profiles consistent with known drug risks.
“There is reassurance here that we are not seeing an excess of problems with delivery with atezolizumab,” Miles said. “Overall, the adverse events that we observed — alopecia, anemia and neuropathy — are all attributable to the backbone chemotherapy that we are giving. This provides us reassurance. To reinforce this, when we looked at adverse events of special interest, we saw a low incidence of hepatitis, pneumonitis and immune conditions related to the thyroid.”
Still, the primary objective of this study was not met, he added.
“Clearly, this result raises questions as to why we see a contrasting result in this study with paclitaxel vs. IMpassion130 with nab-paclitaxel (Abraxane, Celgene). I am certain that this will be the subject of more exploration and a lot of discussion in the future,” Miles said.
References:
- Cortes J, et al. Abstract 1000. Presented at: ASCO20 Virtual Scientific Program; May 29-31, 2020.
- Schmid P, et al. Abstract LBA1_PR. Presented at: European Society for Medical Oncology Congress; Oct. 19-23, 2018; Munich.
Perspective
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Lisa A. Carey, MD, FASCO
There are a few possibilities to explain the divergence between IMpassion130, IMpassion131 and KEYNOTE-355.
First are the differences in the chemotherapy partner. Second are the differences in the study populations. Third, we have to consider the role of “the play of chance.” It should be noted that the IMpassion131 PFS HR of 0.82 had 95% CIs that overlapped the IMpassion130 and KEYNOTE-355 point estimates, which is a reality of clinical research.
When treating patients with PD-L1-positive tumors in the first-line setting, atezolizumab plus nab-paclitaxel remains my first treatment of choice based upon a PFS and OS advantage that was demonstrated at ESMO this year. Adding atezolizumab to paclitaxel did not improve PFS nor OS at this point, and the reasons for this are yet to be determined. They may involve the steroids required to go along with paclitaxel or a heterogeneity in the population that we have not yet measured — we really do not know.
Pembrolizumab (Keytruda, Merck) plus chemotherapy did meet PFS endpoint with a similar HR as atezolizumab at ASCO this year, but we do not have OS data on this yet. Although we could say that the taxane appeared to outperform gemcitabine plus carboplatin, we certainly cannot say that paclitaxel will have that same effect, and given the IMpassion131 results, I would partner with nab-paclitaxel when using pembrolizumab.
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Miles D, et al. Abstract LBA15. Presented at: European Society for Medical Oncology Virtual Congress 2020; Sept. 19-21, 2020.
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